Genome-wide association scans identified CTNNBL1 as a novel gene for obesity

Abstract

Obesity is a major public health problem with strong genetic determination; however, the genetic factors underlying obesity are largely unknown. In this study, we performed a genome-wide association scan for obesity by examining approximately 500 000 single-nucleotide polymorphisms (SNPs) in a sample of 1000 unrelated US Caucasians. We identified a novel gene, CTNNBL1, which has multiple SNPs associated with body mass index (BMI) and fat mass. The most significant SNP, rs6013029, achieved experiment-wise P-values of 2.69 x 10(-7) for BMI and of 4.99 x 10(-8) for fat mass, respectively. The SNP rs6013029 minor allele T confers an average increase in BMI and fat mass of 2.67 kg/m(2) and 5.96 kg, respectively, compared with the alternative allele G. We further genotyped the five most significant CTNNBL1 SNPs in a French case-control sample comprising 896 class III obese adults (BMI > or = 40 kg/m(2)) and 2916 lean adults (BMI < 25 kg/m(2)). All five SNPs showed consistent associations with obesity (8.83 x 10(-3) < P < 6.96 x 10(-4)). Those subjects who were homozygous for the rs6013029 T allele had 1.42-fold increased odds of obesity compared with those without the T allele. The protein structure of CTNNBL1 is homologous to beta-catenin, a family of proteins containing armadillo repeats, suggesting similar biological functions. beta-Catenin is involved in the Wnt/beta-catenin-signaling pathway which appears to contribute to maintaining the undifferentiated state of pre-adipocytes by inhibiting adipogenic gene expression. Our study hence suggests a novel mechanism for the development of obesity, where CTNNBL1 may play an important role. Our study also provided supportive evidence for previously identified associations between obesity and INSIG2 and PFKP, but not FTO.

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits

“…7 online). In addition to these, the KARE GWA data provided corroboration of BMI signals previously reported in the vicinity of the MC4R (in our data, rs17782313, P ¼ 1.9 Â 10 À4 ) and CTNNBL1 (rs6067731, P ¼ 0.02) genes 8,9 (Supplementary Table 8 online).…”

Over-expression of NYGGF4 inhibits glucose transport in 3T3-L1 adipocytes via attenuated phosphorylation of IRS-1 and Akt

“…Obesity is a major public health problem that is strongly influenced by genetic factors that remain largely unknown [12] .…”

Association of genetic variants for susceptibility to obesity with type 2 diabetes in Japanese individuals

“…Twin studies have generally found heritability estimates of 0.75 to 0.85 for BMI and approximately 0.70 for weight [2]. Genome-wide association (GWA) studies have provided evidence that several loci are associated with common obesity mostly in populations of European descent [3][4][5][6][7][8][9][10][11][12][13][14][15]. The first such loci reported was the fat-mass and obesity-associated gene (FTO) [3,16,17].…”